Melanoma is the deadliest form of skin cancer with a very high mortality rate. Metastatic melanoma has a high mortality rate due to lymphatic progression of the disease. The standard treatment for early stage diagnosis is surgical removal of the tumor and for late stage surgery followed by radiation and chemotherapy. Tumor metastasis is the major reason for high mortality rates in melanoma. The process begins with the detachment of tumor cells from the adjacent endothelial cells and the basement membrane and is accompanied by the secretion of various cytokines and growth factors. Migration through the lymphatic vasculature is preferred over blood vessels because of reduced flow rates and pressure, easier access to the vessel, and wider vessel lumens. Up to 80% of melanomas metastasize occurs through the lymphatic system. Additionally, tumor cells secrete lymphangiogenic growth factors like Vascular Endothelial Growth Factors that can stimulate lymphangiogenesis and further promote lymphatic migration. These enlarged lymphatic vessels act as a freeway for the metastatic cells to gain access and spread to distal lymph nodes (LN) and organs.
Extensive research over the past two decades has helped us elucidate the driver mutations occurring in different oncogenes involved in the development of metastatic melanoma. The majority of the studied mutations occur primarily in the BRAF (a serine/threonine protein kinase) genes and the FDA have approved targeted therapies for patients in stage IV or unresectable melanoma. However, newer emerging genetic targets include Neuroblastoma—Rat Sarcoma (NRAS) and nuclear receptors like Retinoid X Receptor-α (RXRα) genes. In pathological conditions, point mutations at the codon 61 of NRAS (NRASQ61K) gene locks the activated form of NRAS-GTP thereby promoting continuous up regulation of downstream effector proteins and signaling pathways in the malignant melanoma phenotype. Activated NRASQ61K mutations play a significant role in the development of metastatic melanoma and are the primary driver mutations that are responsible for the spread of the disease in humans. These oncogenic drivers promote angiogenesis and invasiveness of the malignant cells and also help to develop larger nevi when compared to the BRAF mutations. RXRα plays a major role in gene expression and signal transduction, and in human melanomas the expression of RXRα is lost as the disease progresses. Animal studies have indicated that the loss of RXRα can lead to the increased melanocyte proliferation and the formation of malignant melanomas. Thus, while therapies targeting the BRAF mutations exist, no such therapeutic approaches are currently available for the NRAS or RXRα mutations.